Anaesthesia can generally be described as a state in which noxious events such as surgical procedures are rendered imperceptible by the body, the state being accompanied either by loss of consciousness (general anaesthesia) or no loss of consciousness (local anaesthesia). A complete or general anaesthetic given by inhalation or intravenous route produces a state of profound sleep and loss of motor activity (hypnosis), analgesia, muscle relaxation and protection against the increase in blood pressure and heart rate resulting from surgical stress. Anaesthetics generally display hypometabolic activity and frequently act as respiratory or cardiovascular depressants. Certain anesthetics can be used to produce deliberate hypotensive effects which are very valuable in intracranial and other surgical procedures. Although a large number of agents having anaesthetic and cardiovascular activity have been identified and/or commercialised, there is a continuing need for new materials having hypomethabolic activity, which are valuable for inducing sleep, reduction in motor activity, hypotension, bradycardiac, hypocoagulative, anti-aggregant and other hypobiosis effects such as reduced oxygen consumption and reduced body temperature, which would be valuable for used in complex surgical procedures or in the treatment of life threatening and/or traumatic situations such as brain stroke and myocardial infarction, and which have excellent potency, duration and CNS and cardiovascular toxicity profiles with absence of side effects such as tremor, consulvions and irregular breathing and heart beat.
There is considerable body of data concering 6-R-1,3,4-thiadiazin-2-amines (for reviews see [1-3]). Also a patent literature provides data on myo-relaxant [4-7], sedative [8,9], spasmolytic [10-12] and other types of biological activity [3]. A number of 5-aryl derivatives of 1,3,4-thiadiazines have been specifically described in the art [14-20] as well as 6-alkyl and 6-phenyl analogs thereof [13 and 21]. The value of 6H-1,3,4-thiadiazin-2-amines as hypometabolic anaesthetic and cardiovascular agents has not hitherto been recognised however. Moreever, many of these compounds are apparently novel and have not been previously described in the literature.
The prior art on 6-R-1,3,4-thiadiazin-2-amines includes:
1. H. Beyer, Z. Chem., Bd. 9, S. 361, (1969). PA1 2. S.V. Usoltseva, G.P. Andronnikova, and V.S. Mokreushin, Khim. Geterotsikl. Soedin., No 4, 435, (1991). PA1 3. A.P. Novikova, N. M. Perova, and O. N. Chupakhin, Khim. Geterotsikl. Soedin., No 11, 1443, (1991) PA1 4. W. D. Jones and F. P. Miller. US-A-4,309,426 (1982). PA1 5. W. D. Jones and F. P. Miller. BE-A-884,991 (1980). PA1 6. W. D. Jones and F. P. Miller. DE-A-3,042,295 (1982). PA1 7. FR-A-2,493,844 (1982). PA1 8. US-A-4,272,532 (1981). PA1 9. F. P. Miller and W. D. Jones. BE-A-884,990 (1980). PA1 10. W. D. Jones and F. P. Miller. DE-A-3,031,703 (1981). PA1 11. Fisons PLC, Japan Kokai, Tokyo Koho JP-A-6253976. PA1 12. W. P. Pfeiffer and E. Bulka, DD-A-220311 (1985). PA1 13. N. Yoshida, K. Tanaka, and Y. Iizuka. Japan Kokai 7488889 (1974). PA1 14. L. N. Rasina, O. N. Chupakhin and M. V. Chibiryak. Radiobiologiya, 30(2), 162-5 (1990). PA1 15. A. V. Belik et al, Khim.-Farm. Zh., 26(3), 62-64 (1992). PA1 16. N. M. Perova et al, Khim. Geterotsikl. Soedin., No 4, 565-6 (1993). PA1 17. E Bulka and W. D. Pfeiffer. DD-A-288824. PA1 18. W. D. Pfeiffer and E Bulka, Synthesis, No 7, 485-486 (1977). PA1 19. T. Werner et al, US-A-4,940,790 (1990). PA1 20. A. P. Novikova et al, SU-A-1726478. PA1 21. E. Bulka et al, DD-A-228248. PA1 1. 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide, PA1 2. 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine, mesilate, PA1 3. 2-Morpholino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine, hydrobromide, PA1 4. 2-Morpholino-5-(3-bromophenyl)-6H-1,3,4-thiadiazine, hydrobromide, PA1 5. 2-Thiomorpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide, PA1 6. 2-Thiomorpholino-5-phenyl-6H-1,3,4-thiadiazine, mesilate, PA1 7. 2-Thiomorpholino-5-(4-ethoxypenyl)-6H-1,3,4-thiadiazide, hydrobromide, PA1 8. 2-Thiomorpholino-5-(3-bromophenyl)-6H-1,3,4-thiadiazine, hydrobromide, PA1 9. 2-Thiomorpholino-5-(4-methoxypehnyl)-6H-1,3,4-thiadiazine, hydrobromide, PA1 10. 2-Thiomorpholino-5-(2-chlorophenyl)-6H-1,3,4-thiadiazine, hydrobromide, PA1 11. 2-Thiomorpholino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine, hydrobromide, PA1 12. 2-Hexamethylenimino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide, PA1 13. 2-Piperidino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide, PA1 14. 2-Pyrrolidino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide, PA1 15. 2-Hexamethylenimino-5-(4-bromophenyl)-6H-1,3,4-thiadiazine, hydrobromide, PA1 16. 2-Hexamethylenimino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine, hydrobromide, PA1 17. 2-Hexamethylenimino-5-(4-bromophenyl)-6H-1,3,4-thiadiazine, mesilate, PA1 18. 2-Morpholino-5-(2-chlorophenyl)-6H-1,3,4-thiadiazine, hydrobromide.